Protective effect of walnut active peptide against dextran sulfate sodium-induced colitis in mice based on untargeted metabolomics

[Display omitted] •LP-5 had a good ability to improve metabolites in mice with colitis.•LP-5 significantly regulated the KEGG enriched metabolic pathways analysis.•LP-5 could inhibit the activation of the NLRP3 inflammasome and inhibit the secretion of IL-1β.•LP-5 could improve colonic inflammation by promoting autophagy via the AMPK/mTOR/ULK1 signaling pathway. Inflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of the digestive tract, whose exact cause remains unknown, and its prevalence is on the rise. This study investigated the effects of a walnut-derived peptide LPLLR (LP-5) on intestinal inflammation and metabolism in IBD mice. Metabolomics revealed that LP-5 regulated the levels of metabolites, such as thalsimidine, fumagillin, and geniposide, and LP-5 could regulate several signaling pathways, such as protein digestion and absorption, aminoacyl-tRNA biosynthesis, and ABC transporters. Additionally, LP-5 alleviated dextran sulfate sodium (DSS)-induced colitis by modulating autophagy and inflammasome pathways. Western blotting demonstrated that LP-5 reduced the expressions of NLRP3, Caspase-1, ASC and IL-1β, and increased the expressions of Beclin-1 and LC3-II/LC3-I, corresponding to activation of the AMPK/mTOR/ULK1 pathway. These findings suggested that LP-5 activated autophagy in vivo to suppress inflammation and modulate metabolic substances, highlighting potential implications for gut health and the development of functional foods containing LP-5.